Overview

Cutaneous squamous cell carcinoma (SCC) is an invasive malignant neoplasm of epidermal keratinocytes showing squamous phenotypic differentiation (see the following image). Bowen disease (BD) is a squamous cell carcinoma in situ (SSCIS) with full-epidermal thickness dysplasia that has the potential for significant lateral spread before invasion. The World Health Organization (WHO) classification of Bowen disease includes cases occurring in sun-exposed as well as sun-protected skin. Relative to Bowen disease, actinic keratosis (AK) only occurs on sun-damaged skin, is usually smaller, and retains a squamous differentiation toward the surface, often even when dermal invasion is developing.

A central keratotic squamous cell carcinoma with a raised, undermined periphery in a background of severely sun-damaged skin.

Affected Sites

The majority (70%) of cutaneous squamous cell carcinoma (SCC) occurs on the head and neck, with an additional 15% found on the upper extremities. Tumors of sun-protected skin are more prevalent in black persons and Hispanics. These tumors carry a higher mortality risk, possibly resulting from delayed diagnosis.
[1] Bowen disease has a similar distribution, but this condition is also seen in subungual, periungual, palmar, genital, and perianal locations. Erythroplasia of Queyrat refers to Bowen disease on the glans penis.

Some affected locations are characterized by a more aggressive behavior; for example, squamous cell carcinoma (SCC) of the external ear and lip have overall metastatic rates of 11% and 10-14%, respectively.
[2] Marjolin ulcer (SCC in a chronic ulcer) and anogenital SCC of the usual type demonstrate increased metastatic tendency, likely resulting from delayed recognition and diagnosis.

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Epidemiology

Squamous cell carcinoma (SCC) is the second most common form of nonmelanoma skin cancer after basal cell carcinoma (BCC) and represents 10-20% of cutaneous malignancies.
[3] Its incidence increases sharply with age, such that the occurrence rate of squamous cell carcinoma (SCC) for persons older than age 75 years is approximately 10-folder greater than the overall incidence. The age-adjusted incidence of this disease has grown by 50-200% in the last 10-30 years.
[4] The prevalence of this condition varies inversely with geographic latitude and proportionally with skin fairness. In the US, the overall lifetime risk of developing squamous cell carcinoma (SCC) was 9-14% in men and 4-9% in women in 1994.
[5] The risk increases significantly in recipients of solid organ transplants.

The incidence of Bowen disease is similar to—and its variations parallel—squamous cell carcinoma (SCC): in Minnesota in 1991 the annual rate was 14.9 per 100,000 population, whereas in Hawaii in 1994, the annual rate was 142 per 100,000 population.
[6] The postulated malignancy-associated status of Bowen disease has not been confirmed in large population-based studies.
[7]

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Etiology

Ultraviolet (UV) radiation from sun exposure, occupational exposure, medical treatment (psoralen + ultraviolet A [PUVA]), or tanning beds is principally responsible for the development of squamous cell carcinoma (SCC). It acts by various mechanisms, including p53 suppressor gene inactivation,
[8] cutaneous immunosuppression,
[9] and interference with cellular integrity.
[10] Some of these effects occur with exposure well below the level of sunburn. Ionizing radiation (therapeutic or accidental) and immunosuppression, such as posttransplantation or with chemotherapy, predispose to squamous cell carcinoma (SCC) by similar mechanisms as sun exposure.

Molecular/genetic factors

P53 is a tumor suppressor gene located on chromosome 7 whose mutations have been linked to cutaneous squamous cell carcinoma (SCC) (40-50% incidence). UV-B exposure induces missense mutations with a CC→TT tandem fingerprint change, resulting in loss of p53 function. Caulin et al described a primarily oncogenic role with gain of function mutant p53 that was associated with poorer prognosis.
[14] An underrecognized role for UV-A was also previously described that localizes the corresponding fingerprint mutations in the basal epidermis harboring the vital stem cells, as opposed to the suprabasal UV-B–induced mutations.
[15]

RAS gene mutations are found in 10-30% of cutaneous squamous cell carcinoma (SCC). In experimental mouse tumors, there appears to be a cooperative and even sequential cumulative effect between RAS and p53 mutations.
[14]

As mentioned earlier, HPV is believed to be a co-carcinogen in the development of squamous cell carcinoma (SCC). Proposed mechanisms include UV-induced p53 mutations raising the susceptibility to degradation by the E6 HPV protein and HPV-promoter activation by UV-induced cytokines.
[16]

In the skin, immune evasion may result from p53 mutations in and around immunodominant epitopes, thereby blocking presentation to p53 -specific cytotoxic T lymphocytes.
[17]

Aneuploidy has been documented in actinic keratosis (69%), squamous cell carcinoma in situ (SCCIS) (92%), and squamous cell carcinoma (SCC) (25-80%). Other cytogenetic abnormalities in SCC include loss of heterozygosity (LOH) at 13q, 9p, 17p, 17q, and 3p. Besides p53 on the 17p segment, p16 on the 9p segment was found to be frequently inactivated. Progression of actinic keratosis to SCC correlated with an increased frequency of p16 deletion.
[18, 19]

A study by Schwaederle et al using next-generation sequencing indicated that seven genes (TP53, PIK3CA, CCND1, CDKN2A, SOX2, NOTCH 1, FBXW7) are altered more frequently in various types of SCC (including cSCC) than in non-SCC, while an eighth gene, KRAS, is altered less frequently in SCC.
[20]

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Clinical Features

Squamous cell carcinoma (SCC) presents as a raised, firm, skin-colored or pink, often keratotic papule or plaque on a background of severely sun-damaged skin, with mottled pigmentary alteration, telangiectasia, and the presence of multiple actinic keratoses.

Squamous cell carcinoma (SCC) is typically slow growing, although some variants of SCC, such as the spindle cell type, enlarge rapidly. Bowen disease presents as a slow-growing, irregular, sharply circumscribed, erythematous, velvety, or scaly plaque on sun-exposed or sun-protected skin.

Marjolin ulcers should be considered in any chronic ulcer that fails to heal or which demonstrates a changing appearance. Periungual squamous cell carcinoma (SCC) mimics verruca or paronychia.

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Differential Diagnosis

The following are considered in the differential diagnosis of squamous cell carcinoma and Bowen disease:

Gross Features

The papule or plaque of squamous cell carcinoma (SCC) has a smooth, irregular, ulcerated or hyperkeratotic surface (see the following image). Bowen disease often reaches several centimeters in size and may be occasionally pigmented. Verrucous carcinoma presents as cauliflowerlike exophytic nodules and plaques that may attain considerable size.

A central keratotic squamous cell carcinoma with a raised, undermined periphery in a background of severely sun-damaged skin.

Microscopic Features

Bowen disease/squamous cell carcinoma in situ (SSCIS) is characterized by full-thickness epidermal replacement by crowded keratinocytes that demonstrate disordered dyspolarity, loss of maturation, and nuclear pleomorphism with hyperchromasia. Apoptotic or dyskeratotic cells as well as typical and atypical mitosis are present at all levels of the epidermis, as seen in the following image. There is variable loss of the granular layer with surface parakeratosis. Involvement of hair follicles is common.

Crowded dyspolarity with loss of maturation involves the full thickness of the epidermis where apoptotic cells and mitosis are present (×10 magnification).

Up to 5% of cases of Bowen disease have a pagetoid, upward scatter of larger, grayish neoplastic cells extending laterally in nonobliterated epidermis, as shown in the image below. A clonal pattern or "Borst-Jadassohn" phenomenon may be occasionally seen. Up to 1.67% of Bowen disease lesions may be pigmented.

The main feature distinguishing squamous cell carcinoma (SCC) from SCCIS is extension of malignant squamous epithelium in the dermis (see the following image). Transgression of the basement membrane is easily identified in moderately or poorly differentiated cases, resulting in raggedy or angulated dermal protrusions that are associated with stromal reaction. However, in well-differentiated squamous cell carcinoma (SCC), the neoplastic squamous epidermis advances in the dermis as broad, smooth-edged, keratinizing tongues that are difficult to accurately diagnose on superficial shave biopsies.

Verrucous carcinoma

Verrucous carcinoma (VC) is a slow-growing, low-grade, well-differentiated variant of squamous cell carcinoma (SCC). This entity has a bland squamous cytology and a deceiving pattern of growth as bulbous, smooth-edged tongues pushing in the dermis without an associated stromal response (see the image below). This neoplasm occurs in orolaryngeal mucosa (Ackerman tumor), anogenital areas (Buschke-Lowenstein tumor), plantar skin (epithelioma cuniculatum), and less commonly, other sites. In most locations, the association with various types of human papillomavirus (HPV) is strong.

Acantholytic (adenoid) squamous cell carcinoma (SCC) demonstrates the loss of intercellular cohesion, resulting in glandlike or tubular spaces in which loose dyskeratotic or rounded cells may be present, as seen in the following image.

Spindle cell carcinoma

Spindle cell (sarcomatoid) carcinoma is made up of spindle cells invading the dermis in a haphazardly arranged pattern. Evidence of keratinization is often absent (see the image below). Differentiation of this entity from other cutaneous spindle cell neoplasms requires immunohistochemical profiling.

Keratoacanthoma

Keratoacanthoma (KA) has a controversial status. Although stringent clinical, biologic, and cytogenetic criteria identify bona fide keratoacanthoma, many cases including the metastatic keratoacanthoma represent well-differentiated squamous cell carcinoma (SCC) (see the following image).
[23] A follicular origin is postulated for both of these tumors.

Superficial biopsies of keratoacanthomalike squamous cell carcinoma may be diagnostic challenges in the absence of the base of the lesion. They are more common on the hand (×4 magnification).

Uncommon variants of squamous cell carcinoma (SCC) include the following:

Lymphoepitheliomalike SCC with dense lymphocytic infiltrate obscuring cords of epithelioid cells, often devoid of epidermal connections. As opposed to the nasopharyngeal lymphoepithelioma, no Epstein-Barr virus (EBV) proteins have been found.

Adenosquamous carcinoma has divergent glandular differentiation and an aggressive behavior.

Clear cell SCC has finely reticulated cytoplasm resulting from degeneration rather than glycogen, mucin, or lipid accumulation (see the following image).

Clear cells can be found in the usual squamous cell carcinoma, but they are the predominant component of the clear cell variant, which should be differentiated from sebaceous carcinoma (×20 magnification).

Pigmented SCC harbors "passenger" melanocytes and may be confused with
melanoma clinically.

Desmoplastic SCC tends to occur on the ear. Its dense stroma constitutes 30% of the tumor volume and supports infiltrative cords and trabeculae.

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Immunohistochemistry

The lesional cells of squamous cell carcinoma (SCC) are decorated by pankeratin and AE1-AE3 cocktails. High–molecular-weight keratins (HMWKs) such as CK34βE12 and CK5/6 are more useful than CAM 5.2, owing to the variable expression of low–molecular-weight keratins (LMWKs) in squamous cell carcinoma (SCC).
[24] CK7 is also variably expressed and is positive in other lesions, such as Paget disease, some metastatic hepatic carcinoma, and epithelioid angiosarcoma, all of which may be considered in the differential diagnosis of squamous cell carcinoma (SCC) (see Differential Diagnosis).

CK20 is nonreactive in squamous cell carcinoma (SCC) but stains Merkel cell tumors in a typical juxtanuclear dot pattern.
[25] Nuclear expression of p63 is seen in a large majority of SCC, but it is also seen in basal cell carcinoma (BCC), adnexal tumors, and myoepithelial lesions. Epithelial membrane antigen (EMA) is positive in SCC, but it has weak discriminating power. Relative to BCC and sebaceous carcinoma, which are both positive for Ber-Ep4, SCC is negative for Ber-ep4.

The combination of HMWK (CK34βE1) and p63 positivity was found to be the strongest identifying phenotype of squamous cell carcinoma (SCC) in its multiple variants. This is especially useful in spindle cell SCC (see the image below). which needs to be differentiated from cutaneous leiomyosarcoma (desmin+), spindle cell melanoma (S100+), and atypical fibroxanthoma (CD10+, CD68+).
[26]

The unifying dynamic concept of continuum across actinic keratosis, squamous cell carcinoma in situ (SCCIS), and squamous cell carcinoma (SCC) was evaluated by immunohistochemistry. The hypothesis that changes of expression may correlate with increasing malignant potential has received some support in studies of p53, p27, mib-1, matrix metalloproteinases (MMPs), and p16.
[27]

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Tumor Spread and Staging

Squamous cell carcinoma (SCC) metastases are usually discovered 1-2 years after diagnosis. Primary tumors spread along fascial planes and nerves, as well as through lymphatics and blood vessels. Ipsilateral regional nodes (submental, submandibular, and parotid) are the most common metastasis recipients with a rate of 80%.
[28]

The separation from neck metastasis has been suggested in some staging proposals
[29, 30] but was not adopted in the most current American Joint Committee on Cancer (AJCC) staging system due to insufficient evidence to support this separation. However, the recent 7th AJCC staging system introduced a set of clinical and histologic parameters that resulted in upstaging from T1 to T2, not only using the 2-cm cutoff size but also with any tumor size if associated with 2 or more high-risk features.
[31] These include tumor thickness greater than 2 mm, perineural invasion, ear or lip location, and poor histologic differentiation. Nodal staging (N) now reflects the documented decreased survival with increased nodal size and number of nodes involved.
[31]

Bowen disease invades the dermis in 3-4% of cases, with a higher rate of 10-14% in anogenital locations.
[32]

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Prognosis and Predictive Factors

Compared with basal cell carcinoma (BCC), squamous cell carcinoma (SCC) has overall significantly higher risks of metastasis (2-6%) and tumor death. Detrimental clinical settings include occurrence of SCC in a radiation field or chronic ulcers as well as in immunosuppressed patients. Recipients of solid organ transplants have a 60-250–fold increased risk of developing SCC compared with the general population. The corresponding lesions tend to be multiple and aggressive, with a resultant mortality of 13-46% over 2-4 years.
[33] The ear and lip are high-risk primary sites due to their thin skin and rich vasculature, as well as due to the frequency of desmoplasia in the corresponding tumors. In one study, 50% of all deaths from cutaneous SCC were from genital primaries.
[34]

The grading of squamous cell carcinoma (SCC) proposed by Broders in 1932 included a 4-tiered system in which squamous differentiation decreased by 25% from grade 1 to grade 4. General pathology practice has favored the less-stringent qualifying terms of well, moderately, and poorly differentiated. However, with the exemption of aggressive behavior for poorly differentiated lesions, the degree of differentiation has not correlated well with prognosis.

Tumor thickness greater than 2 mm is an independent determinant for local recurrence and metastasis.
[35] A tumor size 2 cm or larger triples the risk of metastasis. Desmoplasia is the most important histologic feature for local recurrence (24% vs 1% for similar but nondesmoplastic SCC).
[35]

Perineural invasion occurs in 3-14% of lesions and correlates with local recurrence, spindle cell histology, and increasing tumor size. Mohs micrographic surgery with removal of perineural spread has significantly improved the prognosis from a metastatic rate as high as 47% to 8%.
[2]

Superficial biopsies of keratoacanthomalike squamous cell carcinoma may be diagnostic challenges in the absence of the base of the lesion. They are more common on the hand (×4 magnification).

Clear cells can be found in the usual squamous cell carcinoma, but they are the predominant component of the clear cell variant, which should be differentiated from sebaceous carcinoma (×20 magnification).